This study examines the genetic basis of Th1/Th2 development as it relates to autoimmune disease. In the previous funding period, we developed the D011.10 transgenic model for Th1/Th2 development. We were first to identify the role of pathogens and macrophages in Th1 development, to identify Il-12 as the initiator of Th1 development, and to identify signaling mechanisms of Il-12 receptors. We and others suggest that Th1/Th2 development can modify susceptibility to autoimmunity. Drs. David Lo (Scripps Clinic) and hugh McDevitt (Stanford University) recently reported that B10.D2 mice are genetically more prone to an experimental autoimmune disease than Balb/c mice. This susceptibility correlated with greater tendency for Th1 development. More recently our colleague Dr. Jonathan Katz showed that Th1, but not Th2, islet reactive T cells could transfer diabetes in NOD. Thus, our working hypothesis is that multigenic IDDM susceptibility involves some loci controlling Th1 development. This proposal extends our published finding that B10.D2 mice develop stronger default Th1 responses that Balb/c mice. We now have strong preliminary data that Il-12 signaling is genetically different between B10.D2 and Balb/c. Prolonged maintenance of Il-12 signaling in B10/D2 compared to Balb/c would promote the observed increased Th1 development. Thus: Aim 1 analyzes the basis for this difference in Il-12 signaling, building upon our previous progress in Il-12 signaling pathway. Strong preliminary data support the feasibility of this aim. We have also begun genetic mapping of the loci involved. Identification of these loci in the mouse could directly contribute to screening, analysis and studies in diabetic humans. We show genetic evidence for at least two loci, and linking one of these to near the Idd-4 locus. We propose to identify these genetic loci that favor Th1 development in susceptible strains. Thus: Aim 2 will identify genetic loci that factor Th1 development in B10.D2, develop Balb/c congenic strains expressing these B10.D2 alleles, and set the stage for their identification and positional cloning. Our published and preliminary dat demonstrate the feasibility of analyzing genetic loci that favor Th1 development using the D011.10 TCR-transgene to facilitate in vitro phenotype analysis.